2. Academic Validation
  3. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction

The ribonuclease activity of SAMHD1 is required for HIV-1 restriction

  • Nat Med. 2014 Aug;20(8):936-41. doi: 10.1038/nm.3626.
Jeongmin Ryoo 1,  Jongsu Choi 2,  Changhoon Oh 1,  Sungchul Kim 2,  Minji Seo 2,  Seok-Young Kim 2,  Daekwan Seo 3,  Jongkyu Kim 4,  Tommy E White 5,  Alberto Brandariz-Nuñez 5,  Felipe Diaz-Griffero 5,  Cheol-Heui Yun 6,  Joseph A Hollenbaugh 7,  Baek Kim 8,  Daehyun Baek 9,  Kwangseog Ahn 2
Affiliations

Affiliations

  • 1 1] Creative Research Initiative Center for Antigen Presentation, Seoul National University, Seoul, Republic of Korea. [2] Department of the Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
  • 2 1] Creative Research Initiative Center for Antigen Presentation, Seoul National University, Seoul, Republic of Korea. [2] Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • 3 Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • 4 1] Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea. [2] Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.
  • 5 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
  • 6 Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
  • 7 Center for Drug Discovery, Department of Pediatrics, Emory School of Medicine, Atlanta, Georgia, USA.
  • 8 1] Center for Drug Discovery, Department of Pediatrics, Emory School of Medicine, Atlanta, Georgia, USA. [2] School of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
  • 9 1] Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea. [2] Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea. [3] Bioinformatics Institute, Seoul National University, Seoul, Republic of Korea.
PMID: 25038827 DOI: 10.1038/nm.3626
Abstract

The HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool. However, phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels, which is not consistent with a role for SAMHD1 dNTPase activity in HIV-1 restriction. Here, we show that SAMHD1 possesses RNase activity and that the RNase but not the dNTPase function is essential for HIV-1 restriction. By enzymatically characterizing Aicardi-Goutières syndrome (AGS)-associated SAMHD1 mutations and mutations in the allosteric dGTP-binding site of SAMHD1 for defects in RNase or dNTPase activity, we identify SAMHD1 point mutants that cause loss of one or both functions. The RNase-positive and dNTPase-negative SAMHD1D137N mutant is able to restrict HIV-1 Infection, whereas the RNase-negative and dNTPase-positive SAMHD1Q548A mutant is defective for HIV-1 restriction. SAMHD1 associates with HIV-1 RNA and degrades it during the early phases of cell Infection. SAMHD1 silencing in macrophages and CD4(+) T cells from healthy donors increases HIV-1 RNA stability, rendering the cells permissive for HIV-1 Infection. Furthermore, phosphorylation of SAMHD1 at T592 negatively regulates its RNase activity in cells and impedes HIV-1 restriction. Our results reveal that the RNase activity of SAMHD1 is responsible for preventing HIV-1 Infection by directly degrading the HIV-1 RNA.

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